The present invention relates to a novel dosage form of angelica essential oil (soft gelation capsule containing angelica essential oil) and preparation thereof.
The available dosage form of angelica essential oil at present is under the Chinese name of Fu Tong Ning, a kind of dropping pill which has been taken on  less than  less than Drug Standard WS3-B-3191-98 greater than  greater than  of the Ministry of Public Health, PRC. Among them the standard of angelica essential oil, as an active constituent has been taken on the  less than  less than Local Standard of Gansu Province (GWYZZ (85) No. 584 greater than  greater than  and the medicinal material, Angelica sinensis has been taken on the  less than  less than Pharmacopeia of the People""s Republic of China greater than  greater than  1995 Edition, Part 1. The process for preparing said dropping pill is as follows: Angelica essential oil is poured into a mixed liquor of polyethylene glycol 6000 (melted at 100-110xc2x0 C.) and stearic acid, then it is mixed homogenously and prepared with the method of dropping and enteric coating. The product is thus made. Angelica essential oil used for preparing Fu Tong Ning dropping pill is extracted from the crude drug (Chinese angelica root) by means of steam distillation. The modern pharmaceutical research has proved that angelica essential oil possesses the action of dual-directional regulation on uterine smooth muscle. A further study has discovered that the principal active ingredient in angelica essential oil is ligustilide which possesses a stronger anticholinergic action. However, ligustilide can isomerize easily and the therapeutic effects of the drug are influenced by deactivation due to the partial isomerization of ligustilide under the circumstance of high temperature. Even so, in the case of the original dropping pill the preparation of angelica essential oil is carried out under a circumstance of high temperature (100-110xc2x0 C.). Certainly, it causes isomerization of ligustilide as an active component and the therapeutic effect of drug is finally influenced.
The present invention is just aimed at the existing drawback of dropping pill of angelica essential oil in the prior art, in order to research and develop a soft gelation capsule of new dosage form for angelica essential oil.
The object of the present invention is just to provide a soft gelation capsule of new dosage form for angelica essential oil.
The soft gelation capsule of angelica essential oil in the present invention consists of capsule material and oil with medicinal liquor, in which the oil with medicinal liquor consists of angelica essential oil and vegetable oil as diluents. The weight ratio of two kinds of oil is in 1:0-30 (preferably 1:2-20; more preferably 1:7-10; most preferably 1:9). Among them angelica essential oil can be obtained by employing steam distillation followed by extraction, and also by CO2-supercritical fluid extraction. In the present invention angelica essential oil is preferably obtained by the mean of CO2-supercritical extraction. When this method is adopted for extracting angelica essential oil, the working condition is as follows: pressure, 15-35 Mpa; temperature, 30-55xc2x0 C.; time for extraction, 2-20 hours ; CO2 flow, 1-10 L/kg of Angelica sinensisxc2x7hour. Optimized conditions for extraction are as follows: pressure, 20-30 Mpa ; temperature, 35-50xc2x0 C.; time for extraction, 5-8 hours ; CO2 flow, 2-6 L/kg of Angelica sinensisxc2x7hour. The vegetable oil may be one oil selected from the group consisting of sesame oil, peanut oil, corn oil, bean oil, almond oil, peach-kernel oil, cotton seed oil, sunflower seed oil, castor oil and olive oil, preferably sesame oil, peanut oil, corn oil, bean oil and olive oil, while corn oil is the best. The capsule materials consist of gum type of material, plasticizer, water and additive. Among them the gum type of material may be gelatin, or Arabic gum or mixture thereof, wherein the preferred is gelatin. Among them the gelating strength of gelatin is generally in the range of 150-250 brumk and the range of viscosity is 25-45 mPaxc2x7S. The plasticizer may be glycerin, sorbitol or mixture thereof. Among them glycerin is preferred. Additive agents may be an antiseptic, such as a mixture of methyl p-hydroxybenzoate (1.6%) and propyl p-hydroxybenzoate (0.04%). When the gelatin is selected as gel material, the weight ratio of dried substance of gelatin and plasticizer is in 1:0.4-0.6 and that of water and dried gelatin is in 1: 0.7-1.4. An additional agent may be light-screening agent which can be Fe2O3, TiO2, pigment, preferably Fe2O3. Among them the amount of Fe2O3 is 0.0075-0.75 mg/kg gelatin.
The soft gelation capsule of the present invention can be made by adopting a conventional preparative process for soft gelation capsule, for example, molding method by hand, rotary molding method or dropping method. Generally, the pressing method, such as rotary molding method is selected preferably. If an autorotatory capsule pressing is employed, the temperature is controlled at 40-50xc2x0 C., in order to make each capsule containing 10 mg of angelica essential oil.
Soft gelation capsule as the new dosage form of angelica essential oil in the present invention has overcome the drawback in the original dosage form of angelica essential oil as dropping pill because a principal constituent in angelica essential oil is ligustilide which can easily isomerized under an environment of high temperature (such as 100xc2x0 C.) and thus the content of angelica essential oil is decreased. However, the content of ligustilide in angelica essential oil is relatively stable under the room temperature of 20xc2x0 C. (see also Example 1 in detail ). The fact that angelica essential oil in dropping pill is added with stirring and dissolving into a mixture of completely melted (100-110xc2x0 C.) polyethylene glycol 6000 and stearic acid obviously cause an considerable decreasement of content of ligustilide in angelica essential oil. As a result, soft gelation capsule is prepared under temperature of 40-50xc2x0 C. by press method and the amount of ligustilide in angelica essential oil is this be greatly preserved.
Furthermore, the present invention not only avoid the loss of ligustilide in angelica essential oil by changing dosage form of angelica essential oil, but also obtain angelica essential oil containing higher content of ligustilide by means of improving extraction of angelica essential oil, such as CO2-supercritical extraction under a condition of low temperature. In prior art angelica essential oil is extracted with the traditional process of steam distillation. This method causes some trouble to lower the content of ligustilide in angelica essential oil due to unstability of ligustilide to heat. Making a comparison between steam distillation and CO2-supercritical extraction by means of GC-MS analysis, it has been found that the chemical composition of volatile components of angelica essential oil obtained from the above-mentioned two extraction methods are basically the same, but by means of CO2-supercritical extraction the content of (Z)-ligustilide is increased from 53.99% to 74.54% and (E)-ligustilide 3.18% to 9.11% respectively (see also Example 2).
In short, the present new dosage form (soft gelation capsule containing angelica essential oil) has overcome the drawback from the original one (dropping pill) in many aspects, especially with loss of ligustilide, an active component of angelica essential oil.
Influence of Temperature on Ligustilide Content in Angelica Essential Oil
1.1 Apparatus and Reagents
Gas chromatograph (Shimadzu GC-14B); Diethyl phthalate (Shanghai First Reagents Factory, purity is 99.7% tested by gas chromatography with area normalization method); angelica essential oil (991007).
1.2 Experimental Methods
Test group: Five portions of angelica essential oil (30 xcexcl each) are placed separately in five 7 ml-sealing vials numbered with 0, 1, 2, 3 and 4, weighed accurately and sealed. The vials are laid in an oven (100xc2x0 C.) and the samples are taken out of the oven after 0, 1, 2, 3 and 4 hours respectively. Anabout 16 xcexcl of diethyl phthalate as the internal standard is added. Then the samples are weighed accurately and diluted with ca. 1 ml of ethyl alcohol additionally. According to the method in the item of Purity Test under xe2x80x9cProtocol and Remarks of the Quality standard for Angelica essential oilxe2x80x9d the content of ligustilide is determined.
Control group: Five portions of angelica essential oil (30 xcexcl each) are placed separately in five 7 ml-sealing vials numbered with 0xe2x80x2, 1xe2x80x2, 2xe2x80x2, 3xe2x80x2 and 4xe2x80x2, weighed accurately and sealed. The vials are laid aside under room temperature of 20xc2x0 C. and about 16 xcexcl of diethyl phthalate as internal standard is added after 0, 1, 2, 3 and 4 hours respectively. Accurately and diluted with ca. 1 ml of ethyl alcohol additionally. According to the method in the item of Purity Test under xe2x80x9cProtocol and Remarks of the Quality standard for Angelica essential oilxe2x80x9d, the content of ligustilide is determined.
1.3 Experimental Results
The experimental results show that the content of ligustilide in angelica essential oil decreases gradually when angelica essential oil is under temperature of 100xc2x0 C., while the content of ligustilide is relatively stable under room temperature (20xc2x0 C.). The following Table 1 shows the result.
Material:
Crude drug of Chinese angelica is available in December 1998 from Crude Drugs Supply Center, Min County, Gansu Province, China. The quality examination conforms to the drug standard provided by  less than  less than Pharmacopeia of the People""s Republic of China greater than  greater than .
Method:
The conditions for GC-MS are as follows: 25 mxc3x970.2 mm, 5% phenyl polysiloxane (HP-5) chromatographic column; The temperature of column is 80xc2x0 C. and then raised to 250xc2x0 C. with a rate of 3xc2x0 C./min and kept for 10 min. Helium gas is passed with a rate of 0.96 ml/min and the temperature of vaporization chamber is 230xc2x0 C.
The conditions for mass spectroscopy are as follows: the temperature of ion source and transfer line show 200xc2x0 C. and 260xc2x0 C. respectively. Ionization form EI, ionization voltage 70 eV, ionization current 0.22 A, ion source pressure 2.67xc3x9710xe2x88x925 Pa and mass scanning range 40-350 amu.
The conditions for CO2-supercritical extraction are as follows: pressure 25 Mpa, temperature 40xc2x0 C., time for extraction 6 hours and CO2 flow, 2 L/kg Angelica sinensis/hour.
Steam distillation is applied for extracting according to the method described in Chinese pharmacopoeia until no distilled oil is found. Table 2 shows the chemical constituent and percentage content of angelica essential oil.
The experimental results indicate that the chemical compositions of volatile oil of angelica from two extraction methods are basically the same, but the content of ligustilide in angelica essential oil obtained by using CO2-supercritical extraction method is significantly greater than that of steam distillation method.